Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with an average survival of six months following diagnosis. Novel therapies to prolong survival include immune-based approaches. Importantly, key effectors of anti-tumor immunity against PDAC are tumor-associated macrophages (TAMs), which abound in the tumor microenvironment of PDAC. The capacity of TAMs to phagocytose and kill tumor cells is governed by pro- and anti-phagocytic signals found on these cells. Pro-phagocytic signals include clinically-approved antibodies that bind to PDAC cells expressing epithelial growth factor receptor (EGFR). Upon binding tumor cells, anti-EGFR antibodies abate pro-oncogenic signaling and elicit anti-tumor immunity. However, anti-EGFR antibodies have shown limited clinical benefit for PDAC patients. The priority of this proposal will be to promote antibody- dependent cellular phagocytosis (ADCP) of PDAC cells by TAMs during treatment with anti-EGFR antibodies. An anti-phagocytic molecule that I have found to be present on PDAC is CD47. CD47 functions in many cancers to suppress phagocytosis of tumor cells by binding to SIRPa-receptor on TAMs. Aim 1 will examine the consequence of CD47-inhibition on the phagocytosis of PDAC cells by TAMs. The anti-phagocytic role of CD47 is counterbalanced by pro-phagocytic signals such as tumor-bound anti-EGFR antibodies. These antibodies trigger phagocytosis by engaging Fc-receptors (FcRs) on TAMs. Notably, FcR subsets expressed by TAMs may stimulate or inhibit their activity, and the relative abundance of FcR subsets varies between pro- and anti-inflammatory macrophage phenotypes. Aim 2 will study EGFR on tumor cells as well as FcR- expression by TAMs in coordinating ADCP. By understanding the role of pro-and anti-phagocytic signals in governing ADCP, this proposal aims to deploy macrophage-based immunotherapies to potentiate tumor- targeting antibodies against PDAC.